Synthesis, screening and use of parasitic O-glycans and mimetics for improved C-type lectin receptor targeting

Abstract

O-glycans from the helminth Schistosoma mansoni represent promising leads in the development of immunomodulatory compounds via the interaction with C-type lectin receptors (CLRs), as reported for DC-SIGN, L-SIGN, Langerin and MGL. We undertook the chemoenzymatic synthesis of an O-glycan library inspired from structures previously isolated from the helminth. We described the synthesis of parasitic O-glycan cores mucin core 2 and the S.mansoni specific core. Enzymatic elongations towards a library of O-glycans were limited to the Galß-1,6GalNAc arm of the cores owing to an unanticipated acceptor specificity of the recombinant glycosyltransferase LgtA_X. Synthesized as aminopentyl glycosides, eight O-glycans were obtained and were printed on-chip alongside N-glycans available from our laboratory. The array was enzymatically modified using a FucT from H.pylori in conjunction with either a fucose or 6-azido-fucose donor and arrayed against a selection of CLRs, revealing interesting features in the CLR specificity and suggesting the existence of exploitable chemical space for CLR targeting.